MXPA97004395A - Reduction of electrostatic forces between magne trisilicato absorbers - Google Patents

Abstract

The present invention relates to a medicament absorbent containing corn syrup containing therein from about 10 to about 90% by weight of the absorbent of a medicament drug, a magnesium trisilicate having a surface area of at least 400. m2 / g and having a structure with multiple interstitial spaces and having absorbed therein from about 0.5 to about 30% by weight of the absorbent of a drug drug, wherein the drug drug is an antihistamine. A reduction in electrostatic forces between absorbers is experienced due to the size of the absorbent particles that are in the greater range of 40 to around 80 um, most prepared absorbers have a particle size greater than 150 um, which allows better process

Description

REDUCTION OF ELECTROSTATIC FORCES AMONG ABSORBING TRISD ICATO MAGNESIUM BACKGROUND OF THE INVENTION In the development of oral formulas, many aspects must be considered. These include: (1) the drug should be stable in the presence of excipients of the formula; (2) the drug must be recovered from the excipients of the formula; (3) the drug must exhibit acceptable dissolution characteristics from the formula; (4) processing must allow uniformity in acceptable content; and (5) the formula must have acceptable physical characteristics. Many of these aspects are considered in preformulation through drug-excipient compatibility studies. Chemical stability is often the primary issue with drug-excipient compatibility evaluations.

The drug-excipient physical interactions, however, can also affect the performance of the formula and the development of analytical methodology. For example, although interactions that result in the absorption of drugs in the form of solid doses from excipients are generally of a weak type such as Van der Waals forces and hydrogen bonds, they have been shown to influence and affect the uniformity of the content of the solid dosage forms.

For example, in the manufacture of tablets, the segregation of drug absorbents of a small particle size from excipients of solid dosage forms can occur due to the electrostatic nature of the absorbers. Once the absorbents are segregated, they are re-agglomerated into small spheres that have a high concentration of drug. The foregoing is virtually evident and can be observed in the uniformity of mixing and the uniformity of the solid dosage form. The segregation of drug absorbents from a small particle, therefore, contributes to variations in the drug content of solid dosage forms such as tablets, which is unfavorable due to the unreliable supply of a drug.

An example of drug absorbers that have shown unfavorable drug-excipient physical interactions are those that are prepared from magnesium trisilicates, to absorption of a drug in magnesium trisilicates in the preparation of a drug absorber has been taught in literature as a method to obtain insipid bitter drug principles in liquid, tablet and chewable dosage forms that are readily bioavailable when the absorbent reaches the low pH acid medium of the stomach. Unfortunately, the resulting formed absorbent has a very small particle size (30 microns) and is highly electrostatic. As indicated above, these electrostatic forces cause the absorbent to segregate from the excipients and re-agglomerate into small spheres that have a high drug concentration. The solid dose forms prepared with the drug absorbents vary by ten percent or more in their drug concentration due to the lack of uniformity in the mixture.

It can be understood that it would be an improvement to the technique if the electrostatic properties of the absorbent could be reduced without effecting the taste disguise. The reduction of electrostatic forces would improve the processing of absorbers such as those containing magnesium trisilicate and provide a more uniform composition.

U.S. Patent No. 3,085,942 to Margoid presents the formation of an antitussive composition using dextromethorphan hydrobromide and its acid addition salts absorbed, in part, in magnesium trisilicate. Magid notes that the size of the magnesium trisilicate particle is not critical in the preparation of the sorbents and that the average particle size of about 0.1 to about 150 microns is useful. Magid also notes that when ingredients are intimately mixed, the acid taste associated with dextromethorphan is reduced or eliminated. The absorbent can be mixed with other ingredients to form compressed tablets, candy bars, chewing gum tablets and the like.

U.S. Patent No. 4,581,232 to Peters et al., Discloses a medicine absorber containing magnesium trisilicate having a surface area of at least 400 m2 / g and having frost-shaped structure with multiple interstitial spaces and having absorbed within it from about 1% to about 20% by weight of the absorbent of a drug drug, wherein the drug drug is an antitussive such as dextromethorphan hydrobromide. This patent further discloses that the absorbent may be formulated with pharmaceutically acceptable carriers, ie, diluents, bonds and adhesives, lubricants, disintegrants, colorants, flavors, sweeteners, to prepare medicinal compositions that offer a variety of textures to satisfy particular applications. Said compositions can have the form of a tablet, tablet, capsule, pill, chewable candy and the like.

U.S. Patent No. 4,647,459 to Peters et al., Presents a confectionery composition containing a magnesium trisilicate having a surface area of at least 400 m2 / g and has a frost structure with multiple interstitial spaces and having absorbed yes from about 1% to about 20% by weight of the absorbent of a drug drug. Said compositions can have the form of a tablet, tablet, capsule, pill, chewable candy and the like.

The United States patents presented herein are expressly incorporated by reference.

SUMMARY OF THE INVENTION It has been unexpectedly discovered that by using a bond, such as corn syrup, the size of the particles can be increased and the electrostatic forces of the magnesium trisilicate sorbents reduced without effecting flavor concealment. In particular, it has been determined that unexpected results are exhibited in a medicament absorber comprising from about 0.5% to about 60%, a bond having itself content from about 10 to about 90% by weight of an absorbent of a magnesium trisilicate having a surface area of at least 400 m2 / g and having a structure similar to frosts with multiple interstitial spaces and having itself absorbed from about 0.5 to about 30% by weight of the medicament drug absorber. This magnesium trisilicate absorber in particular has been found suitable for the preparation of uniformly blended and tasteless drug absorbents.

We have also unexpectedly discovered a process for preparing the drug absorbent whose process involves dissolving the drug drug in a solvent, mixing magnesium trisilicate and a link to achieve a homogeneous mass and recovering the drug absorbing product. In particular, a process has been discovered that involves dissolving a drug drug such as disfenhydramine hydrochloride or dextromethorphan hydrobromide in a solvent, mixing trisilicate and magnesium having a surface area of at least 400 m2 / g and having a structure such as frost with multiple interstitial spaces along with a bond such as corn syrup to reach a homogeneous mass and recover the medicine absorbent product by a drying process.

The medicament absorbent of the invention may further include a pharmaceutically acceptable carrier in the form of a tablet, tablet, pill, capsule, chewable candy and chewing gum.

DETAILED DESCRIPTION OF THE INVENTION In the preferred example of the invention, the magnesium trisilicate is a fine, white and odorless fine powder having a surface area of at least 400 m2 / g and preferably at least 400 m2 / g up to 1000 m2 / g and more preferably from about 440 m2 / g to about 600 m2 / g having a frost-like structure with multiple interstitial spaces.

However, in other examples of the present invention, normally available magnesium trisilicate can be used. The term magnesium trisilicate does not have a precise description but it approaches the formula 2Mg? 3SiO2 x H2O. The physical texture and the absorbent properties of the magnesium trisilicates have been varied thereby depending predominantly on their mode of preparation. These materials, however, generally have a water content of 17 to 34%, a minimum of 20% of magnesium oxide, a minimum of 45% of silicon dioxide and a ratio of MgO to SiO2 of about 2.10 to about 2.30.

Normal magnesium trisilicates have a surface area of less than 400 m2 / g and preferably less than 250 m2 / g. These materials are similarly globular hemispherical structures that do not resemble frost in appearance and lack interstitial spaces.

The method for making the magnesium trisilicates used in this invention is not critical and is not considered part of this invention. It is believed that the magnesium trisilicates of this invention are of natural occurrence or that they can be prepared by standard techniques well known to those of ordinary skill that would not require unnecessary experiments. Such techniques generally utilize normal reagents, such as sodium silicate. and magnesium sulfate that react under heat, the magnesium trisilicate is precipitated and recovered. See, for example, U.S. Patent No. 3,272,594 which is incorporated herein by reference.

The weight percentage of the magnesium trisilicate, based on the weight of the absorbent is from about 10 to about 90%, more preferably from about 30 to about 80% and more preferably from about 40 to about 70%.

The drug drugs used herein can be chosen from a wide variety of drugs and their acid addition salts. Both organic and inorganic salts can be used as long as the drug maintains its medicinal value and is soluble in the solvent. Exemplary acid salts include hydrochloride, hydrobromide, orthophosphate, benzoate, maleate, tartrate, succinate, citrate, salicylate, sulfate and acetate.

The percentage of the weight of the drug or its acid addition salt in the mass, based on the weight of the absorbent is from about 0.5 to about 30%, more preferably from about 5 to about 20% and more preferably from about 8 to approximately 12%, whose amounts will vary depending on the therapeutic dose allowed.

The appropriate categories of drugs that can be employed in the present absorbent can vary widely and usually represent any combination of stable absorbent drug. Illustrative categories and specific examples include: a) antitussives, such as dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate and clofedianol hydrochloride; b) antihistamines, such as chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate, diphenhydramine hydrochloride, promethazine and triprolidine; c) decongestants, such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudofedrine hydrochloride, ephedrine; and d) several alkaloids, such as codeine phosphate, cadein sulfate and morphine.

These materials can be used alone or in combination in the absorber within the ranges specified above.

A particularly effective drug absorbent has been prepared using dextromethorphan hydrobromide and / or diphenhydramine hydrochloride The binding agents (linkages) of the present invention are compounds that exert a strong physical-chemical attraction force between the molecules. The binding agents in the present invention include corn syrup, starch, sugar, sugar alcohols, polyvinyl pyrrolidine, acacia, gelatin, glucose, guar gum, pregelatinized starch and sodium alginate and cellulose derivatives such as ethylcellulose, hydroxypropylcellulose, hydropropylmethylcellulose , methylcellulose, sodium carboxymethylcellulose and the like and mixtures thereof. Preferably the binding agent is corn syrup.

Corn syrup is essentially liquid glucose and may have a liquid or solid form. A commercially available corn syrup is EMDEX® that is manufactured by Mendell Company.

EMDEX® is a highly refined product composed almost entirely of free-flowing, crystallized, porous spheres. For optimum performance, it requires a lubricant such as magnesium stearate j used in the proportion of 0.5 to 1% container to the weight of the formula. Although the composition of EMDEX® is well known in the art, the typical chemical composition comprises the following carbohydrates: dextrose (95%), isomalt (2.0%), maltotriose (less than 0.1%), maltose (1.0%) , gentiobiosa (2.0%) and panosa (less than 0.5%). While EMDEX® is the preferred bonding agent, it should be understood that other bonds can be employed that reduce the electrostatic forces between the magnesium trisilicate absorbers so that an absorbent can be prepared and exhibits the properties or characteristics described in I presented.

The amount of binding agent in the absorbent is an amount effective to reduce the electrostatic forces between the magnesium trisilicate absorbers. An effective amount of binding agent is an amount that will allow a medicament absorber to be uniformly distributed through a medical product. The amount of binding agent is a matter of preference, subject to factors such as the type of magnesium trisilicate or drug, the type and amount of binding used and the other ingredients in the drug delivery system. Thus, the amount of binding agent can be varied to obtain the desired result in the final product. In general, the binding agent will be present in an amount of from about 0.5 to about 60% and preferably from about 3 to about 40% and more preferably from about 10 to about 25% by weight of the medicament absorber.

While the invention is not limited to theoretical considerations, it is believed that the use of the link increases the size of the particles of the drug absorbent. The increased size of the particles of the drug absorbents makes them less susceptible to segregation by excipients of solid dosage forms added due to the reduction in electrostatic forces between each drug absorbent.

The particle size of medicament sorbents containing magnesium trisilicate until the date of the present invention was in the order of 0.1 to 40 um. The particle size of the medicament absorbent of the present invention, however, is greater than 40 um. Preferably, the particle size of the medicament absorber is in the range greater than 40 to about 800 um. More preferably, the particle size of the medicament absorbent is in the range from about 150 to about 600 um.

There are additional physical properties of the drug absorbers of the present invention that can be characterized and used to differentiate them from absorbers previously known in the art, such as density and moisture. Absorbents produced by previously known techniques were characterized by a density of about 200-500 grams / liter against the drug absorbers produced by the present invention (directly mixing a binding agent with a drug drug dissolved in solvent and mixed with trisilicate of magnesium) that reach a density of around 700-1000 bouquets / liter. The known absorbers are also dried in about 15 to about 18 hours due to the very fine particles that are pressed down in an oven which prevents adequate air flow and uniform drying, as opposed to the drug absorbers of the present invention that dry in about 8 to about 12 hours.

It has also been found that the drug absorbers of the present invention have a desirable dissolution ratio profile. More specifically, it has been found that the drug absorbers of the present invention have a faster release rate of an active drug than the previously known absorbers.

Further discussion of this property is provided further in the Examples section.

The medicament absorber of the invention can be prepared by conventional granulation and / or filling techniques. Both processes involve the initial step of dissolving the drug of drug in a suitable inert solvent and then mixing with the magnesium trisilicate and the binding agent, the concentrations of the drug in solvent can vary widely but are generally from about 10 to about 70% by weight of the total composition. When the mixing is carried out with low amounts of solvent, for example about 15 to about 35% by weight of the total composition, the resulting granular product is removed and dried at a predetermined moisture content between about 4 and about of 12% by weight of the total composition. When higher concentrations of solvent are used, a slurry containing the drug, magnesium trisilicate and the binding agent is formed. The concentrations of the drug in solvent can vary in the range from about 40 to about 80% by weight of the total composition for optimal results. The solvent is then removed and the absorbent recovered and used as a paste or dried to a free-flowing powder.

Any solvent can be used in the inventive process to prepare the absorbent as long as it is capable of dissolving the medicament drug. Representative solvents include water; low polyhalogenated hydrocarbons such as chloroform, methylene chloride; low alcohols, such as methanol, ethanol, propanol and butanol; and aromatic solvents such as benzene, with water being the preferred solvent.

The concentration of magnesium trisilicate added to the solvent can vary widely but is generally from about 30 to about 90% by weight of the total composition. More preferably, the concentration of magnesium trisilicate added to the solvent is from about 50 to about 80% by weight of the total composition. More preferably, the concentration of magnesium trisilicate added to the solvent is from about 60 to about 80% by weight of the total composition.

The concentration of bond added to the solvent can vary widely but is generally from about 1 to about 90% by weight of the total composition. More preferably, the concentration of bond added to the solvent is from about 20 to about 70% by weight of the total composition. More preferably, the concentration of aggregate bond to the solvent is from 20 to about 50% by weight of the total composition.

The drug absorber once prepared can be stored for future use or can be formulated with conventional additives, which are pharmaceutically acceptable carriers, to prepare medicinal compositions that offer a variety of textures to suit particular applications. Said compositions can have the form of a tablet, tablet, capsule, pill, chewable candy, chewing gum and so on. The pharmaceutically acceptable carriers can be chosen from a wide range of materials. Without being limited thereto, said materials include diluents, bonds and adhesives, lubricants, disintegrators, colorants, flavors, sweeteners and particular medicinal. The preparation of confectionery products and chewing gums are well known historically and has changed very little over the years.

The pills are medicated and flavored dosage forms to be sucked and kept in the mouth. They can have several forms, the most common are flat, circular, octagonal and biconvex. Pill bases generally have two forms, solid boiled candy pellets and pills in compressed tablet.

Boiled solid candy bars are prepared from a mixture of sugar and other carbohydrates that is kept in an amorphous or vitreous condition. This form can be considered as a solid syrup of sugars that generally has from 0.5 to 1.5% moisture. These materials normally contain up to 92% corn syrup, up to 55% sugar and from 0.1% to 5.0% water. The syrup component is generally prepared from high fructose corn syrups, but may include other materials. Other ingredients such as flavorings, sweeteners, acidulants, dyes and others can also be included. In contrast, tablets of compressed tablets contain particular materials and are formed in structures under pressure. They generally contain sugars in amounts up to 95% and excipients of typical tablets such as bonds and lubricants as well as flavors, colorants and others.

The tablets can be made from soft confectionery materials such as those contained in the capsules. These materials contain two primary components, namely a high boiling syrup such as corn syrup or the like and a relatively light texture granitate, usually prepared from gelatin, egg albumin, milk proteins such as casein and vegetable proteins as soy protein and the like. The granita is relatively light and can, for example, vary in density from about 0.5 to about 0.7 g / cc.

By way of comparison, the high boiling syrup, or "bob syrup", is relatively viscous and has a higher density and often contains a substantial amount of sugar. Conventionally, the final capsule composition is prepared by adding the "bob syrup" to the granita under agitation, to form the basic capsule mixture. Other ingredients such as flavorings, oils, additional sugar and the like can be added thereafter also under agitation. A general discussion of the composition and preparation of capsule confections can be found in B.W. Minifie, CHOCOLATE COCOA AND Confectionarv: Science and Technology, 2nd Edition, AVI Publishing Co., Inc., Westport, Connecticut) (1980) on pages 424-425.

The pharmaceutical tablets of this invention may also take the form of chewable forms. This form is particularly advantageous due to the convenience and acceptance of the patients and the rapid onset of bioactivity. To achieve acceptable stability and quality as well as good taste and mouth feel, several considerations are important, mainly the amount of active substance per tablet, the compressibility and the organoleptic properties of the drug.

The preparation of medicated chewable candies is prepared by procedures similar to those used in making soft confectionery. This procedure generally involves the formation of a mixture of boiled-sugar-corn syrup to which a hailstorm is added. The mixture of boiled sugar-corn syrup can be prepared from sugar and corn syrup blended into parts in a weight ratio of 90 to 10: 10 to 90. This mixture is heated to temperatures above 250 ° F to stir the water and to form a melted mass. The granita is prepared generally from gelatin, egg albumin, milk proteins such as casein and vegetable proteins such as soy protein and the like which are added to a gelatin solution and mixed rapidly at room temperature to form a dough similar to aerated sponge. The slush is then added to the melted caramel base and mixed until homogeneous at temperatures between 150 ° F and 250 ° F. The drug absorbent can then be added as the temperature of the mixture is lowered around 150 ° F to 200 ° F when additional ingredients are added, such as flavors and colorings. The formula cools even more and is formed into pieces of desired dimensions.

A general discussion of the forms of lozenges and chewable confectionery tablets is found in H A. Lieberman and L. Lachman, Pharmaceutical Dosage Forms: Tablets. Volume I, Marcel Decker, Inc., New York, New York, pages 289 to 466.

With respect to the chewing gum formula in particular, the amount of the gum base used will vary greatly depending on various factors such as the type of base used, the desired consistency and other components used to make the final product. In general, amounts of from about 5% to about 45% by weight of the final chewing gum composition are acceptable for use in chewing gum compositions with preferred amounts of from about 15% to about 25% by weight. The gum base can be a water-insoluble gum base well known in 1 art. Illustrative examples of suitable polymers in gum bases include both elastomers and natural and synthetic gums. For example, those polymers which are suitable in gum bases, include, without limitation, substances of vegetable origin such as chewing gum, jeluton, gutta percha and crown gum. Synthetic elastomers such as polyethylene copolymers, isobutylene-isoprene copolymers, polyethylene, polyisobutylene and polyvinylacetate and mixtures thereof are particularly useful.

The rubber base composition may contain elastomer solvents to adjust to softening the rubber component. Said elastomer solvents may comprise methyl, glycerol or pentaerythritol esters of modified rosins or rosins, such as hydrogenated, dimerized or polymerized rosins or mixtures thereof. Examples of elastomer solvents suitable for use herein include the pentaerythritol ester of partially hydrogenated wood rosin, pentaerythritol ester of wood rosin, polymerized rosin glycerol ester, glycerol ester of stem oil rosin, glycerol ester of wood rosin and partially hydrogenated wood rosin and partially hydrogenated rosin methyl ester such as alpha-pinene or beta-pinene polymers; Terpene resins including polyterpene and mixtures thereof. The solvent can be employed in an amount ranging from about 10% to about 75% and preferably from about 45% to about 70% by weight of the gum base.

A variety of traditional ingredients such as plasticizers or softeners such as lanolin, stearic acid, sodium stearate, potassium stearate, glyceryl triacetate, glycerin and the like eg natural waxes, petrolatum waxes, such as polyurethane waxes, paraffin waxes and waxes Microcrystalline can also be incorporated into the gum base to obtain a variety of textures and desirable consistency properties. These individual additional materials are generally employed in amounts of up to about 30% by weight and preferably in amounts of from about 3% to about 20% by weight of the final gum base composition.

The chewing gum composition may additionally include the conventional additives of flavoring agents, coloring agents such as titanium dioxide; emulsifiers such as lecithin and glyceryl monostearate; and additional fillers such as aluminum hydroxide, alumina, aluminum silicates, calcium carbonate and talc and combinations thereof. These fillers can also be used in the gum base in various quantities. Preferably the amount of fillers when used will vary from about 4% to about 30% by weight of the final chewing gum.

In the example where auxiliary sweeteners are used, the present invention contemplates the inclusion of those sweeteners well known in the art, including both natural and artificial sweeteners. Thus, the additional sweeteners can be chosen from the following non-limiting list: A. Water-soluble sweetening agents such as monosaccharides, disaccharides and polysaccharides such as xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, sugar, maltose, partially hydrolyzed starch or corn syrup solids and sugar alcohols such as sorbitol, xylitol, mannitol and mixtures thereof.

B. Water-soluble artificial sweeteners such as soluble saccharin salts, ie sodium or calcium saccharin salts, cyclamate salts, acesulfam-K and the like and the free acid form of saccharin. C. Dipeptide base sweeteners such as L-aspartyl-phenylalanine methyl ester and the materials described in U.S. Pat. No. 3,492,131 and the like.

In general, the amount of sweetener will vary with the desired amount of sweeteners chosen for a particular chewing gum. This amount will normally be 0.001% up to about 90% by weight when using an easily removable sweetener. The water-soluble sweeteners described in category A above are preferably used in amounts of from about 25% to about 75% by weight and more preferably from about 50% to about 65% by weight of the final chewing gum composition . In contrast, the artificial sweeteners described in categories B and C are used in amounts of about 0.005% to about 5.0% and more preferably from about 0.05% to about 2.5% by weight of the final chewing gum composition. These amounts are normally necessary to achieve a desired level of sweetness regardless of the level of flavor achieved by flavoring oils. While water can be added independently with dry sweeteners, it will usually be added as part of a corn syrup or corn syrup mixture.

Suitable flavors include both natural and artificial flavors and mints such as spearmint, menthol, artificial vanilla, cinnamon, various fruit flavors, either individual or mixed and the like are contemplated. The flavors are generally used in amounts that will vary depending on the individual flavor and may, for example, vary in amounts from about 0.5% to about 3% by weight of the weight of the final composition.

Dyes useful in the present invention include pigments such as titanium dioxide, which may be incorporated in amounts of up to about 1% by weight and preferably up to about 0.6% by weight. Also, colorants may include other dyes suitable for food, drug and cosmetic applications and are known as dyes F.D. &C. and similar. The materials acceptable for the present spectrum of use are preferably soluble in water. Illustrative examples include idioid dye, known as Blue F.D. &C. number 2, which is a disodium salt of 5,5'-indigotindisulfonic acid. Similarly, the dye known as Green F.D. & C. number 1, which comprises a triphenylmethane dye and is a monoside salt of 4- [4-Nityl-p-sulfobenzilarmno) diphenylmethylene] - [l- (N-ethyl-Np-sulfomumber? Zil = -2,5-cyclohexadhemolamine A complete list of all FD &C. and D. &c: and their corresponding chemical structures can be found in the Kirk-Othmer Encyclopedia of Chemical Technology, in Volume 5, at pages 857-884 whose The text is incorporated herein by way of reference.

Suitable oils and fats that are useful would include partially hydrogenated vegetable or animal fats, such as coconut oil, kernel palm oil, beef tallow, shortening and the like. These ingredients are generally used in amounts with respect to the edible product of up to about 7.0% by weight and preferably up to about 3.5% by weight of the final product.

The amount of absorbent used can vary widely depending on the drug dose of the particular drug. Medication amounts of about 1.0 to about 400 mg per drug dose are useful depending on the particular medication. The natural amounts of medicament absorber used will be higher depending on the therapeutic dose required and the amount of medicament absorbed in the absorbent. Illustrative examples are illustrated below.

The usual dose of diphenhydramine hydrochloride is between 10 and 50 mg per tablet. The incorporation of the absorbent into, for example, a caramel base is not difficult because of its melting point and its solubility in solvents. It is compatible with most flavors and is stable over a wide pH range. The diphenhydramine hydrochloride when added as a medicament absorber avoids its acid taste and its difficulty in flavor.

The usual dose of fenidamine tartrate is around 10 to 50 mg per tablet.

The formula is not difficult to flavor because of the absence of flavor after medication. The usual dose of pmlamine maleate is 25 to 50 mg per tablet. The usual dose range of chlorpheniramine maleate is 2 to 4 mg and it easily lends itself to incorporation in a caramel base. Naturally, the exact amount will vary with the application and the particular drug.

The medicament absorber is generally present with the pharmaceutically acceptable carrier in an amount from about 1% to about 60% by weight of the final composition. The exact amount will depend on the particular medication and dosage required.

The present invention is best illustrated by the following examples. All parts and percentages in the examples and in the body of the description and the claims are by weight unless otherwise indicated.

EXAMPLE 1 This example demonstrates a method for preparing an absorber of dextromethorphan hydrobromide. At 120 kg. of water is mixed n 12 kg. of dextromethorphan hydrobromide, at a water temperature of about 90 ° C until the drug is in solution. 35 kg was added to the solution. of corn syrup (EDMEX®) and 91 kg. of magnesium trisilicate having an actual surface area of 506.1 m2 / g and mixed until a homogeneous dispersion resulted, approximately 20 minutes, the mixture was then dried in an oven at 70 ° C until the moisture content less than 10% it was reached. The product was then stirred to prepare a free flowing white powder containing 8.0% by weight of dextromethorphan hydrobromide.

An organoleptic evaluation test was carried out on the product to determine the presence or absence of acidity. The present product exhibited no acidity or bad taste when tested by a panel of human experts.

EXAMPLE 2 This example demonstrates a method for preparing a pseudoephedrine sorbent Silicon Dioxide (CABOSIL M5®) 20.0% 200 g Magnesium trisilicate 40.0% 400 g Pseudoephedrine HC1 (PSE) 40.0% 200 g Polyvinylpyrrolidone (PVP) 5.0% 50 g Starch of corn 15.0% 150 g 100.0% lOOOg Dissolve the PSE in 500 g of water, charge magnesium trisilicate (MTS) and silicon dioxide (SiO2) in a high speed mixer. Add the drug solution to the MTS / SIO2 by spraying at a rate of 100 cc / min and while mixing at 25 RPM. After the addition of the drug solution, add the PVP and the corn starch. Mix at 75 RPM (with the main beater and beater at approximately 100 RPM) Mix until uniform granulation is produced Download into a fluid bed dryer and dry until the final humidity is between 2-10% Beat using a Comil equipped with a round perforated sprayer from 0.45"to approximately 150 RPM.

EXAMPLE 3 This example demonstrates a method for preparing a multi-symptom absorbent Magnesium Trisilicate (MTS) 76% 760.0 g Pyrilamine Maleate (PM) 5% 50 g Dextromethorphan HBr (DM) 3% 30 g Pseudoephedrine HCl (PSE) 6% 60 g Hydroxypropylmethylcellulose (HPMC) 5% 50 g Acivel PH lOl 4% 40 g Poloxamer 407 1% 10 g 100% lOOOg Dissolve PM, DM, PSE and Polaxomero 407 in 750 ml of hot water. Load a low speed mixer, such as a Hobart planetary mixer, with 760 g of MTS (based on anhydrous). The above is done to adjust the varying level of moisture content in each batch of MTS. For example, if the MTS contained 20% humidity, an excess of 20% of MTS should be added. Spray the drug solution over the MTS in a mixture until ready. Add the Avicel and the HPMC and mix until uniform. Additional water can be added to achieve the desired consistency. Unload the mixer and dry the absorber at 70 ° C in a forced hot air oven until it has a final humidity of 3%. Beat the absorbent using a Fitz mixer with forward impacts at 2500 RPM with a 0 filter.

EXAMPLE 4 This example demonstrates a method for preparing various tablet formulations using one or more types of absorbent prepared in a manner similar to Examples 1 through 3. The following ingredients are mixed in the indicated order: Composition of cold chewable tablets containing 30 mg of Pseudoephedrine Absorbent HCL Pseudoephedrine Absorbent (PSE) 18% by 23.8% 166.6 mg weight of PSE Di-Pac (compressible sugar) 60.0% 420.0 mg Mannitol 11.2% 78.4 mg Cherry flavor 1.5% 10.5 mg Malic acid 0.5% 3.5 mg Adipic acid 1.0% 7.0 mg Magnesium stearate 0.5% 3.5 mg Aspartame 1.5% 10.5 mg 100.0% 700 mg Multi-symptom chewable tablet composition containing 15 mg of Detromethorphan HBr, 30 mg of Pseudoephedrine HCl, 25 mg of Pyrilamine Maleate Absorbent Multisintomas 62.5% 500 mg Mannitol 31.67% 253.36 mg Zinc stearate 0.75% 6 ing Orange flavor 2.0% 16 mg Citric acid 2.0% 16 mg Sodium Saccharin 0.08% 0.64 mg Aspartame 1.0% 8.0 mg 100.0% 800 mg In the previous example, 500 mg of acetaminophen can also be added to each tablet for relief of fever and pain. The above could be done by removing the mannitol and add acetaminophen. The weight of the chewable tablet would then be 1047 mg.

Tablet composition for cold / sinus / asthma containing 4 mg of Chlorpheniramine Maleate, 60 mg Pseudoephedrine HCl 1. Chlorpheniramine maleate (CPM 10% absorber (4.0 mg drug / tablet) 40 mg 2. Pseudoephedrine HCl 10% absorber (60.0 mg drug / tablet) 600 mg 3. Microcrystalline cellulose 50 mg 4. Lactose 75 mg 5. Modified cellulose gum 20 mg 6. Smoked silica 3 mg 7. Stearic acid 3 mg 8. Magnesium stearate 2 mg 793 mg Load the microcrystalline cellulose, lactose and modified cellulose gum into a twin shell mixer. Mix for 5 minutes. Add the CPM and PSE absorbers and mix for 10 minutes. Add the stearic acid and the fumed silica and mix for 7 minutes. Add the magnesium stearate and mix for 4 minutes.

The same mixing order would follow for a Bin mixer, however, the Mixing times would be 1.5 times longer than the previous mixing times. This is because the Bin method is less efficient.

EXAMPLE 5 A comparison was made between the sample batches of the absorbent mixture of medicaments of the present invention and those known prior to the date of this invention. Several batches of samples of hydroxychloride defensi-hydramine sorbent mixtures with an actual surface particle size greater than 100 μm and several batches of samples of mixtures of diphenhydramine hydrochloride absorbents with actual particle size no greater than 40 μm were subjected to analytical tests. The mixtures were tested from 10 points to a PK 50 cubic feet mixer using the following sample plan.

A mixer was charged with final powder mixtures of the drug absorbers. The mixer is started, after 5 minutes of mixing the mixer was stopped. Samples were taken from the ten different locations within the mixer as illustrated below. The backup samples were also taken in case it was necessary to do the tests again (a total of 20 samples were taken in the interval of minutes).

The mixer was closed and mixing started for another 5 minutes. (These are now the 10 minute samples reported in Table 1). Ten samples were taken again with the appropriate backups. This procedure was repeated four times more (a total of 30 minutes of mixing). In general, the complete mix of most powders occurs between 15 and 30 minutes of mixing time.

Mixer samples (PK 50 cubic feet mixer) - 10 locations 1. Top left. 2. Top left in the center. 3. Top right in the center. 4. Top right. TL, TLC, TRC, TR 5. Middle left ML, MM, MR 6. Middle BL, BR 7. Middle right DP 8. Lower left 9. Lower right 10. Discharge port NOTE : Approximately 750 mg +/- 185 mg (one tablet weight) of the mixture was used (using a thief) in triplicate from each location in the mixer. These samples were transferred separately in glass jars with screw caps. A single sample from each location was tested and the remaining two were retained in case other tests were required.

Table 1 shows the results of the studies of mixtures belonging to diphenhydramine hydrochloride absorbers having a particle size greater than about 100 μm. The data shows uniformity at all test points for all batches. The variability between the concentration of diferihydramine hydrochloride in the different test points was around 1.5 to 2.5%. This variability is acceptable under USP standards that require variability no greater than 4%.

TAI 1LA 1 Location in the mixer Lot A of Lot B of Lot C of Lot D of samples samples samples Top left 12.5 12.5 12.4 12.6 Arria on the left center 12.5 12.7 12.8 13.0 Top right center 12.4 12.4 12.6 12.6 Top right 12.7 12.2 12.6 12.8 In the middle to the left 12.6 12.4 13.0 13.1 In the middle 12.8 12.6 12.7 13.0 In the middle to the right 12.5 12.4 12.5 12.6 Bottom left 12.4 12.6 12.1 13.0 Bottom right 12.4 12.4 12.1 13.6 Download port 12.2 12.3 11.8 13.6 Average 12.5 12.5 12.5 13.0 % RSD 1.36 1.21 2.93 2.87 Table 2 shows the results in the studies of mixtures belonging to the diphenhydramine hydrochloride absorbents having a particle size no greater than about 400 um.

The samples demonstrate a high degree of drug variability. The above is due to fine and electrostatic absorbent particles that will segregate easily. After segregation, two phenomena can occur: 1) the absorbent forms agglomerates that are collected on the surface of the powder and 2) the fine particles of the absorbent can escape through the mixture and concentrate at the bottom of the mixer.

The data shows a significant degree of variation in the amounts of sorbents at all test points for the two batches and thus fails to meet the specification indicated in the process validation protocol. The variability between the concentration of diphenhydramine hydrochloride in the different test points was around 10% and with this high degree of variability, the tablets could be out of specification, generally, a mixture of RSD greater than 4% produces tablets of poor quality that would fail in the tests of power and uniformity of content.

TABLE 2 Lot E of samples Time Top Top Top Center Middle Down (minutes) left center right left middle middle RSD 15 12.61 12.28 11.44 13.38 12.44 16.41 13.09 13.3 12.37 12.74 11.60 13.10 12.91 13.16 12.65 4.63 12.67 12.40 11.83 13.10 12.26 13.42 12.62 4.56 12.35 12.84 12.88 13.93 13.40 13.01 13.07 4.13 Final 12.41 12.09 12.67 13.75 12.93 12.90 12.79 4.43 Average 12.48 12.47 12.08 13.45 12.79 13.78 & RSD 1.18 2.52 5.38 0.38 3.52 10.7 EXAMPLE 6 A dissolution proportion profile of the medicament absorbent of the present invention (MA) was carried out to verify the release of diphenhydramine HCl. A dissolution model (in vitro) was used to compare drug absorbents with known absorbers (KA). Six tablets containing the drug absorbents were tested against known absorbers. The dissolution conditions were Apparatus 1 (baskets), 900 ml of 0.1 N HCl at a speed of 150 rpm. The samples were taken at 30, 45, 60 and 90 minutes, neutralized and tested.

As shown in Table A, tablets containing medicament absorbents had a much better dissolution compared to tablets containing known absorbers. Also, it was noted that tablets containing medicament sorbents disintegrated completely in less than 30 minutes while a portion of the tablets containing known absorbent remained even after 90 minutes.

Regarding the USP requirements, the dissolution tests of the two types of tablets for 45 minutes using 500 ml deionized water with the basket apparatus at 100 RPM was carried out (Table B). In comparison, here again the tablets containing medicine absorbers had faster dissolution than the tablets containing known absorbers.

TABLE A% of Diphenhydramine HCl released Absorbent 30 minutes 45 minutes 60 minutes 90 minutes MA 93 1 99.3 101 101% of RSD 2.04 1.69 0.70 2.29 KA 37.2 51.2 60.2 71.5% of RSD 9.86 10.1 8.51 4.32 * Percentage of six tablets.

TABLE B% of Diphenhydramine HCl released Absorbent 45 Minutes MA 26.3% of RSD 6.91 KA 5.15% of RSD 13.6 * Percentage of six tablets.

The invention described thus. It is obvious that the same can vary in many shapes. These variations should not be considered as separate from the spirit and scope of the invention and all these modifications are intended to be included within the scope of the following claims:

Claims (24)

1. CLAIMS: 1. A medicament absorber comprising an effective amount of a bond for reducing the electrostatic forces of the absorbent and containing itself absorbed from about 10% to about 90% by weight of the magnesium trisilicate absorbed and containing absorbed and absorbed. yes from about 0.5 to about 30% by weight of the absorbent of a medicament drug, the medicament absorber is of the size characterized by a density in the range from about 700 to about 1000 grams / liter.
2. 2. The absorbent of Claim 1 wherein the magnesium trisilicate has a surface area of at least 400 m2 / g and a structure with multiple interstitial spaces.
3. 3. The absorbent of the Claim wherein the drug drug is an antihistamine.
4. 4. The absorbent of Claim 1 wherein the drug drug is selected from the group consisting of antihistaminic materials consisting of chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate, diphenhydramine hydrochloride, promethazine and triprolidine.
5. 5. The absorbent of Claim 1 wherein the bond is present in the amount of from about 0.5 to about 60% by weight of the absorbent.
6. 6. The absorbent of Claim 1 wherein the medicament trisilicate has a surface area of about 440 m2 / g to about 600 m2 / g.
7. 7. The absorbent of Claim 1 wherein the linkage is selected from the group consisting of corn syrup, PVP, starches, sugars, gelatin and cellulose derivatives.
8. 8. The absorbent of Claim 1 wherein the link is corn syrup.
9. 9. The absorbent of Claim 1 wherein the absorbent is combined with at least one pharmaceutically acceptable excipient.
10. 10. The absorbent of Claim 1 wherein the absorbent is part of a tablet.
11. 11. The absorbent of Claim 1 wherein the size of the absorbent is in the range greater than 40 to about 800 um.
12. 12. The absorbent of Claim 1 wherein the size of the absorbent is in the range greater than 150 and up to about 600 um.
13. 13. A medicament absorber consisting essentially of from about 0.5 to about 60% by weight of the sorbent a magnesium trisilicate bond and absorbed therein from about 100 to about 90% by weight of the sorbent wherein the magnesium trisilicate has a surface area of at least 400 m2 / g and a structure with multiple interstitial spaces and containing itself absorbed from about 0.5 to about 30% by weight of the diphenhydramine hydrochloride absorbent, the absorbent has a size in the range greater than 150 and up to approximately 600 um.
14. 14. The absorbent of Claim 13 wherein the absorbent has a density in the range from about 700 to about 1000 grams / liter.
15. 15. The absorbent of Claim 14 wherein the amount of the corn syrup is from about 3 to about 40% by weight of the absorbent.
16. 16. The absorbent of Claim 15 wherein the medicament drug is present is an amount of from about 5 to about 20% by weight of the absorbent.
17. 17. The absorbent of Claim 16 wherein the trisilicate of the medicament has a surface area of about 440 m2 / g to about 600 m2 / g.
18. 18. The absorbent of Claim 17 wherein the absorbent is combined with at least one pharmaceutically acceptable excipient.
19. 19. A process for preparing a medicament absorbent comprising dissolving a medicament drug in solvent, mixing magnesium trisilicate and mixing a bond to prepare a dough and recovering the medicament absorbing product.
20. 20. The process of Claim 19, which comprises employing magnesium trisilicate having a surface area of at least 400 prVg and having a structure having multiple interstitial spaces per se to prepare a mass having a homogeneous consistency to allow migration of the drug drug within the interstitial spaces of the magnesium trisilicate and recover the drug absorbing product.
21. 21. The process of Claim 20 comprising employing about 5 to about 40% by weight of solvent to prepare a granulated mixture containing the medicament drug, linkage and magnesium trisilicate that is dried to have a moisture content of about 1. up to about 25% by weight.
22. 22. The process of Claim 21 which comprises employing about 40 to about 80% of the solvent to prepare a slurry and thereafter removing the solvent from the slurry to form a slurry.
23. 23. The process of Claim 22 wherein the pulp is dried and recovered as a free flowing powder.
24. 24. The process of Claim 23 wherein a pharmaceutically acceptable carrier is added to the powder. EXTRACT OF THE INVENTION A medicament absorber containing corn syrup containing therein from about 10 to about 90% by weight of the absorbent of a medicament drug, a magnesium trisilicate having a surface area of at least 400 m2 / g and having a structure with multiple interstitial spaces and having absorbed therein from about 0.5 to about 30% by weight of the absorbent of a drug drug, wherein the drug drug is an antihistamine. A reduction in the electrostatic forces between absorbers is experienced due to the size of the absorbent particles which is in the greater range of 40 up to about 800 um, most prepared absorbers have a particle size greater than 150 um, which allows better processing.